KR102453376B1 - Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs - Google Patents

Abstract

A coating for an expandable portion of a catheter comprising a hydrophobic matrix and a dispersed phase is disclosed. The dispersed phase comprises a plurality of micro-reservoirs dispersed in the hydrophobic matrix, the plurality of micro-reservoirs comprising a first active ingredient and a biodegradable or bioerodible polymer. A formulation for the coating and a method for forming the coating are also disclosed. Methods for treating a catheter and condition comprising the coating on an expandable portion are also provided.

Description

COATING FOR INTRALUMINAL EXPANDABLE CATHETER PROVIDING CONTACT TRANSFER OF DRUG MICRO-RESERVOIRS

Incorporation by Reference to Any Priority Applications

Any and all applications for which foreign or domestic priority claims are identified in the Application Data Sheet filed with this application are hereby incorporated by reference under 37 CFR 1.57.

This disclosure relates to the field of drug delivery via expandable catheters.

Balloon angioplasty is an established method for the treatment of vascular diseases by physically expanding the area of atherosclerosis, stenosis or reduction of the lumen diameter in diseased vessels. Balloon dilatation is typically performed with a catheter that can be advanced into the circulatory system to the diseased area. The catheter has a balloon at its distal end, which is inflated to inflate and expand the area of the stenosis. In many instances, such as in coronary arteries, a stent is also expanded outside of the balloon. The stent is left intact after deflation and removal of the balloon to maintain the patency of the dilated lumen.

To achieve physical dilation of the blood vessel, a large force is applied to the tissues of the blood vessel during high pressure balloon inflation. The physical dilatation results in injury to blood vessels, including endothelial fission, segmentation of the inner elastic layer, and dissection of the vascular mesentery. Injuries often extend to the outer envelope. The vascular biological response progresses through the thrombus phase for 0 to 3 days, including platelet activation and adsorption and thrombus formation. The thrombotic phase is followed by a cell recruitment phase for 3 to 8 days, which involves the infiltration of inflammatory cells, macrophages and lymphocytes to the site of vascular damage. The release of growth factors and cytokines from the inflammatory cells induces a proliferative phase for 8 to 14 days in which dormant smooth muscle cells of the vascular mesentery are stimulated to proliferate. Thereafter, migration of proliferating smooth muscle cells into the intima and lumen thrombi results in neointimal proliferation, a major factor in restenosis. Although cell proliferation ceases after 14 days, continued production of extracellular matrix by smooth muscle cells continues, increasing the extent of neointimal proliferation and restenosis. Restenosis effectively reverses this dilatation and creates a potentially fatal threat to the patient. Human clinical trials have demonstrated that restenosis typically occurs 1 to 3 months after balloon dilatation, and restenosis typically peaks at about 3 months.

Although balloon dilatation results in significant increases in blood flow to diseased vessels, restenosis is inherent due to the degree of mechanical injury involved. One strategy to reduce restenosis response is to release the drug into the blood vessel in combination with balloon dilatation therapy to neutralize inflammation and therapeutic response. Approaches include coating the balloon with drugs such as paclitaxel and sirolimus (rapamycin), which limit cell proliferation. It is believed that during contact of the balloon to the luminal surface of the vessel, the coating facilitates delivery of the drug to the site of the vessel injury. These methods attempt to provide drug concentrations low enough to reduce restenosis caused by cell proliferation and at the same time to minimize toxicity to blood vessels that can result in damage or obstruction of blood vessels. It is believed necessary to maintain an effective drug concentration for a time sufficient to minimize restenosis.

Indeed, the delivery of drugs to the tissues of the vessel wall by drug coated balloons described in the art is limited by the short period of time the balloon is placed in contact with the vessel. Typically during balloon dilatation, the balloon inflation is performed for about 30 to about 120 seconds to limit cardiac ischemia and potential patient complications and discomfort. For the antianginal paclitaxel, which showed inhibition of neointimal formation in animals after a few minutes of exposure time, this short balloon inflation and drug delivery time would be sufficient. However, in order to provide maximum therapeutic effect and to minimize potential high-dose toxicity to blood vessels, it would have been desirable to provide delivery of the drug to the blood vessels over an extended period of time, ideally longer than the duration of balloon inflation. will be. Additionally, drugs such as sirolimus and its equivalents have both anti-proliferative and anti-inflammatory activity, which may provide post-acute benefit for restenosis if delivered over an extended period of time.

Many of the drug coated balloons described in the prior art use initially high levels of the active ingredient and multiple regimens to produce initially high therapeutic concentrations, but then the concentrations drop rapidly. This is undesirable because the majority of active ingredients in the device either lose possible embolic particles into the bloodstream or diffuse from the treatment site.

Many drug coatings described in the prior art contain hydrophilic polymers and additives or additives that are liquid at body temperature. A formulation for such a hydrophilic coating would provide a hydrophilic matrix for the hydrophobic drug particles and would be effective in delivering the drug to the vessel wall. However, such coatings do not provide significant resistance to wash-off during careful manipulation of the balloon to the treatment site or after delivery of the drug coating to the vessel surface.

US Patent Publication No. 2007-0299512 US Patent Publication No. 2011-0022027 International Patent Publication No. 2013-014677 US Patent Publication No. 2012-0165786 Korean Patent Publication No. 10-2012-0036627

Accordingly, the problem to be solved by the present invention is to solve the above problems, and to provide a coating for an expandable portion of a catheter that continuously releases a drug for a longer period of time and a catheter comprising the coating. In addition, it is to provide a method for coating the coating prescription and the coating prescription on the catheter.

Summary of the Invention

Some embodiments provide a coating for an expandable portion of a catheter comprising a hydrophobic matrix and a dispersed phase, the dispersed phase comprising a plurality of micro-reservoirs dispersed in the hydrophobic matrix, the plurality of The micro-reservoirs contain a first active agent mixed with or dispersed in a biodegradable or bioerodible polymer. Some embodiments provide a coating wherein the dispersed phase comprises a plurality of micro-reservoirs dispersed in a hydrophobic matrix, wherein the plurality of micro-reservoirs comprises a first active ingredient and a biodegradable or bioerodible polymer.

Some embodiments provide a catheter comprising an expandable portion in an elongated body and a coating for the expandable portion described herein. In some embodiments, the catheter further comprises a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion. In some embodiments, the catheter further comprises a protective coating over the coating containing the micro-reservoirs.

Some embodiments provide a coating formulation for an expandable portion of a catheter comprising a solid portion and a fluid. The solid portion comprises a plurality of microreservoirs and at least one hydrophobic compound. The plurality of micro-reservoirs contain a first active ingredient and a biodegradable or bioerodible polymer. The fluid disperses or solubilizes at least one hydrophobic compound and suspends the plurality of micro-reservoirs.

Some embodiments provide for coating an expandable portion of a catheter, comprising: positioning a coating formulation described herein against a surface of an inflated expandable portion of a catheter, evaporating the fluid, and collapsing the expandable portion It provides a method of coating comprising the step of.

Some embodiments provide for advancing a catheter comprising an expandable portion to a treatment site for treating or preventing a condition at a treatment site, wherein the expandable portion is coated with a coating described herein, wherein the coating and the treatment site are There is provided a method of coating comprising the steps of expanding the expandable portion to allow for contact between tissues, retracting the expandable portion, and removing the catheter.

The coating for the expandable portion of the catheter of the present invention can improve the control of drug release to the luminal surface of the blood vessel during the balloon inflation time of angioplasty, for example, balloon dilatation, and using the coating prescription and coating method of the present invention The above coating may be provided, but the effect of the present invention is not limited thereto.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Forms, aspects, and advantages of embodiments of the present disclosure are described in detail below with reference to the drawings of various embodiments, which are illustrative and not intended to limit the present invention. These drawings depict only a few embodiments in accordance with the present disclosure and should not be taken as limiting their scope.
1 depicts one embodiment of a balloon catheter with a coating on the expandable portion of the catheter.
2 depicts one embodiment of a balloon catheter with a release layer between the coating and the expandable portion of the catheter.
3 depicts one embodiment of a balloon catheter with a protective layer over the coating.
4 is a micrograph of the luminal surface of a blood vessel treated with one embodiment of a balloon catheter.
5 is a photomicrograph of the luminal surface of a blood vessel treated with one embodiment of a balloon catheter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

To overcome the limitations of the prior art, embodiments disclosed herein provide sustained release of a drug mixed with or dispersed into a coating on a balloon that can be delivered to the luminal surface of a vessel for a 30 to about 120 second balloon inflation time. Coatings are provided for the expandable portion of the catheter. This approach allows for extended and controlled release of the drug into the vessel wall over a longer period of time that can be tuned by the specific drug properties or the design of micro-reservoirs for the pathology of diseased vessels. In addition to providing sustained release, the coatings disclosed herein can also resist blood wash off, increasing both drug delivery efficiency and patient safety from excess particulate.

coating

A coating for an expandable portion of a catheter or catheter system is disclosed herein. The catheter is designed for insertion into a living body for local delivery of at least one active ingredient. While the catheter is placed into a target blood vessel or lumen of the body for treatment or after delivery of the coating from a treatment site to a tissue, such as a vessel wall or lumen wall, the coating provides minimal solubility and dispersibility into the bloodstream or body fluid. blended and formulated. The coating is configured to be delivered to the lumen surface or lumen wall contacted by the coating when the expandable portion is expanded. In some blood vessels or body lumens, the inner surface of the blood vessel or body lumen may be diseased and have an irregular topology, such as due to plaque, lesion, or previous intervention. can have The coating is configured to transfer to a lumen surface comprising the irregular topology, as described herein by the term lumen wall. In some embodiments, the active ingredient or drug is delivered into a blood vessel to prevent or minimize restenosis after balloon dilatation. In some embodiments, the inflatable portion may be a balloon of a balloon catheter.

1 , in some embodiments, the coating 12 for the expandable portion 11 of the catheter 10 includes two phases, a hydrophobic matrix 14 and a disperse phase 13 . The dispersed phase 13 is dispersed in a hydrophobic matrix 14 . The dispersed phase 13 comprises a plurality of micro-reservoirs comprising a first active ingredient and a biodegradable or bioerodible polymer. In some embodiments, the first active ingredient is mixed with or dispersed in the biodegradable or bioerodible polymer. When the coating 12 is delivered to the visceral wall or lumen surface, the delivered coating will comprise both a hydrophobic matrix 14 and a dispersed phase 13 .

In some embodiments, some or portions of the plurality of micro-reservoirs may include a first active ingredient and a biodegradable or bioerodible polymer, and some contain the biodegradable or bioerodible polymer without the first active ingredient. may include

In some embodiments, the hydrophobic matrix 14 may further include a second active ingredient. The second active ingredient is external to the plurality of microreservoirs. The second active ingredient may be the same as or different from the first active ingredient.

In some embodiments, the plurality of micro-reservoirs may also contain a third active ingredient. In some embodiments, the plurality of micro-reservoirs may further include a second biodegradable or bioerodible polymer. In some embodiments, the first and second biodegradable or bioerodible polymers may be the same or different. In some embodiments, the plurality of micro-reservoirs may contain only one type of micro-reservoirs.

In some embodiments, the coating 12 comprises from about 10% to about 75%, from about 20% to about 65%, or from about 30% to about 55% by weight of the plurality of micro-reservoirs. In some embodiments, the coating 12 is about 1 μg/mm ² to about 10 μg/mm ² , about 2 μg/mm ² to about 9 μg/mm ² , or about 3 μg on the expandable portion of the catheter 10 . /mm ² to about 8 μg/mm ² have a surface concentration.

The hydrophobic matrix 14 comprises a combination of materials selected for their desirable adsorption properties to a lumen surface or lumen wall. A preferred hydrophobic matrix 14 comprises a combination of hydrophobic compounds that are resistant to dissolution into blood or other body fluids but provide a uniform distribution of the formulation comprising the micro-reservoirs when applied to the surface of the balloon. In some embodiments, the hydrophobic matrix 14 comprises at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof. Particularly useful combinations are combinations of sterols and fatty acids or phospholipids. The sterol may be a sterol that utilizes the body's natural clearance mechanisms, such as forming complexes with serum lipids or aggregates with serum apolipoproteins to provide transport to the liver for metabolic processes. In some embodiments, the sterol may be cholesterol. Due to the natural compatibility of cholesterol and fatty acids or phospholipids, such combinations can provide a homogeneous mixture for coating 12, which in turn can provide a homogeneous coating on the balloon surface. The coating 12 formed by such combinations is homogeneous without the formation of micelles or liposomes in the hydrophobic matrix 14 .

In some embodiments, the hydrophobic matrix 14 comprises cholesterol and fatty acids. In some embodiments, the weight ratio of cholesterol to fatty acid ranges from about 1:2 to about 3:1, from about 1:1.5 to about 2.5:1, or from about 1:1 to about 2:1. The content and ratio of cholesterol and fatty acids is sufficient to enable delivery of the coating from the expandable portion of the catheter to the lumen wall. The cholesterol component of the formulation may include cholesterol, chemically modified cholesterol or cholesterol complex. In some embodiments, the cholesterol is dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol). For physiological compatibility, preferred fatty acids are those commonly found in serums or cell membranes. In some embodiments, the fatty acid is lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid, mi Myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid , linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, mead acid , arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid acid), hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.

In some embodiments, the hydrophobic matrix 14 comprises cholesterol and phospholipids. In some embodiments, the weight ratio of cholesterol to phospholipid ranges from about 1:2 to about 3:1, from about 1:1.5 to about 2.5:1, or from about 1:1 to about 2:1. The content and ratio of cholesterol and phospholipid is sufficient to enable delivery of the coating from the expandable portion of the catheter to the lumen wall. The cholesterol component of the formulation may include cholesterol, chemically modified cholesterol or cholesterol complexes. In some embodiments, the cholesterol is DC-cholesterol. Preferred phospholipids are those commonly found in serums or cell membranes. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol. In some embodiments, the phospholipid comprises an acyl chain from about 20 to about 34 in length.

In some embodiments of the present disclosure, the hydrophobic matrix 14 includes only hydrophobic components such as lipids, sterols and fatty acids. In other words, in some embodiments, the hydrophobic matrix does not include a hydrophilic polymer or a hydrophilic additive. In some embodiments of the present disclosure, the hydrophobic matrix 14 includes only hydrophobic components such as lipids, sterols and fatty acids, and no amphoteric components are present. Preferably, the coating 12 and its components have limited solubility in blood or analogs such as plasma or phosphate buffered saline. The use of cationic cholesterol or cationic phospholipids in the formulation is to increase the delivery of the coating 12 to the blood after chemical attraction and delivery of the hydrophobic matrix 14 to the surface of the luminal wall and potentially micro-reservoirs. It can provide resistance to dissolution. Suitable cationic forms of cholesterol include DC-cholesterol modified at the carbon 3 position attached to a pendant tertiary or quaternary amine. Suitable cationic forms of phospholipids include naturally occurring phospholipids and synthetic modifications of phospholipids such as amine derivatives of phosphatidylcholines such as phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), and ethylphosphatidylcholine.

In some embodiments, the acyl chain length and degree of unsaturation of the phospholipid component of the hydrophobic matrix 14 may be used to tailor the physical and chemical properties of the hydrophobic matrix 14 . In some embodiments, a long acyl chamber length is selected to increase the hydrophobicity of the phospholipids for adsorption to the luminal wall and to reduce wash-off due to solubility and bloodstream exposure. The acyl chain length of the fatty acid moiety of the fatty acids and phospholipids is described by the number of carbon-carbon double bonds followed by a colon followed by abbreviations. In the following descriptions of both phospholipids, common names or common names, stereospecific numbering and ellipsis are used for the first description of the compound. Acyl chain lengths of 20 to 34 carbons (C20 to C34), together with the particularly preferred acyl chain lengths of 20 to 24 carbons (C20 to C24), are suitable for use as coating 12 components. Although the present invention also works with saturated acyl chains, one or more positions of unsaturation can provide increased chain flexibility. Examples of preferred phospholipids are dieicosenoyl phosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine), C20: 1 PC), diarachidonoyl phosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine), C20: 0 PC), dierucoyl phosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine (1,2-dierucoyl-sn-glycero-3-phosphocholine), C22 : 1 PC), didocosahexaenoyl phosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine) ), C22:6 PC), heneicosenoyl phosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine (1,2-heneicosenoyl-sn-glycero-) 3-phosphocholine), C21:1 PC) and dinervonyl phosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine (1,2-dinervonoyl-sn-glycero) -3-phosphocholine), C24:1 PC). In some embodiments, the phospholipid has a transition temperature at or above ambient temperature (20°C), so that the hydrophobic matrix 14 solidifies during storage.

The plurality of micro-reservoirs contains an active ingredient and a polymer. Said active ingredient may be referred to as the first active ingredient or as the third active ingredient. The active ingredient is associated with the polymer in such a way as to provide slow or extended release of the active ingredient from the micro-reservoirs. In some embodiments, the active ingredient is mixed with or dispersed in a biodegradable or bioerodible polymer. In some embodiments, the active ingredient may be encapsulated by the biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs may contain the first active ingredient. In some embodiments, the plurality of micro-reservoirs may further comprise a third active ingredient. In some embodiments, the second active ingredient may be external to the plurality of micro-reservoirs. The second active ingredient may be included in the hydrophobic matrix portion. Suitable active ingredients, such as the first, second or third active ingredient, include paclitaxel, sirolimus (rapamycin) and their chemical derivatives or mTOR inhibitors, inhibitory RNA, inhibitory DNA, steroids and It may contain anti-enhancing or anti-inflammatory agents such as analogs that are complement inhibitors. In some embodiments, the active ingredient is paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. selected from the group consisting of In some embodiments, the active ingredient is from about 10% to about 50%, from about 15% to about 45%, from about 20% to about 40%, or from about 25% to about 35% by weight of the plurality of micro-reservoirs. %to be. The micro-reservoirs may contain microparticles or microspheres. In some embodiments, polylactic-co-glycolic acid (PLGA) microspheres are suitable for inclusion in the active ingredient for sustained release of up to 50% by weight of the active ingredient in the microspheres.

In some embodiments, the plurality of micro-reservoirs have an average diameter of from about 0.5 microns to about 8 microns, from about 2 microns to about 6 microns, or from about 3 microns to about 5 microns. In some embodiments, the micro-reservoirs preferably have a size large enough to provide sustained release of the active ingredient, approximately 1.5 microns in diameter or average cross-sectional dimension for non-uniformly sized microparticles. it is excess Smaller sized micro-reservoirs typically have an increased surface area to volume ratio and a reduced shedding pathway for the active ingredient that does not provide a sufficiently amplified release. The maximum size of the micro-reservoirs is approximately the size of red blood cells, about 6 microns to about 8 microns, to prevent embolization of the microvessels due to any micro-reservoirs released into the bloodstream during or after treatment. to be. In some embodiments, the micro-reservoirs do not necessarily have affinity or adsorption to the lumen wall.

The biodegradable or bioerodible polymer can provide a controlled and extended release of the active ingredient. The biodegradable or bioerodible polymer may be referred to as a first biodegradable or bioerodible polymer or a second biodegradable or bioerodible polymer. The polymer acts as a barrier to drug diffusion and thus provides a release profile tailored to the pharmacokinetics of the active ingredient acting on the treated vessel. For example, the active ingredient may be mixed and dispersed into a polymer in a solid solution. The polymer may provide controlled release by reducing active ingredient diffusion or coupling drug release with biodegradation, dissolution or bioerosion of the polymer. In some embodiments, the biodegradable or bioerodible polymer is polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, poly phosphazene, collagen, gelatin, chitosan, glycosoaminoglycans, and combinations thereof. In some embodiments, the micro-reservoirs may also be microspheres or micro-particles containing at least one active ingredient that treats an inflammatory or healing response. In some embodiments, the plurality of micro-reservoirs may contain a first biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs may contain a second biodegradable or bioerodible polymer.

After contact of the coating 12 with the luminal wall in the body, the rate of active ingredient release is controlled by the release of the active ingredient from the micro-reservoirs into the surrounding medium, thus penetrating the blood vessel wall. Allows for sustained elution of the component. In order to provide a significant active ingredient during the initial high risk phase for restenosis with swelling, it is preferred that the active ingredient in the coating 12 be continuously released at a half-life release rate of about 2 weeks to about 6 weeks or more. . In some embodiments the plurality of micro-reservoirs has an active ingredient release rate with a half-life of at least 14 days.

The rate of release of the active ingredient can be tailored by the properties of the micro-reservoirs. To tailor the therapeutic effect, micro-reservoirs with different active ingredients or two or more types of micro-reservoirs with different release rates for the same active ingredient can be formulated with the coating 12 . In some embodiments, some active ingredient may be included in the formulation for a coating on the exterior of the micro-reservoirs to provide a rapid initial release of the active ingredient to the vessel wall, where the micro-reservoirs are present for an extended period of time. It makes it possible to provide an active ingredient sufficient to maintain an effective tissue concentration of the active ingredient. Since healing and resolution of inflammation in the area of swelling typically take 4-12 weeks, micro-reservoirs and Corning12 to elute the active ingredient are at least about 4 to about 12 weeks following the treatment. while providing a therapeutic tissue level is desirable. In certain applications, such as very long, extensively diseased blood vessels, maintaining active ingredient levels above 4 to 12 weeks is desirable to provide additional protection from the less common effects of late restenosis.

The release of the active ingredient mixed with the solid or dispersed in the solid is shown to follow Higuchi kinetics with the active ingredient decreasing with time. For particles of a sphere with active ingredient dispersed in a polymer, the active ingredient release rate also follows the Korsmeyer-Peppas kinetic model similar to the Higuchi equation, which is the power law of the decreasing release rate (J. Siepmanna). J, Peppas NA, Modeling of active ingredient release from transport systems based on hydroxypropylmethylcellulose (HPMC), Advanced Drug Delivery Reviews 48 (2001) 139-157). The rate of release of the active ingredient from such micro-reservoirs is suitable for the treatment of post-vascular dilatation. The design and selection of micro-reservoirs with suitable release constants allows for rapid initiation of active ingredient with extended active ingredient residence and sustained active ingredient release in the vessel wall over a longer period of time compared to prior art devices. provide emission. The rate of release of the active ingredient is determined by the solubility of the active ingredient in the micro-reservoir material and by adjusting the microporosity of the micro-reservoir. It can be adjusted by the solubility of the active ingredient in the micro-reservoir material, and the content of the active ingredient loaded into the micro-reservoirs. The total content of active ingredient to be delivered is determined by the content of micro-reservoirs in the formulation for cortisol and the level of their active ingredient loading. Consequently, the coating 12 can be formed to have a concentration of the active ingredient in the range of about 0.3 to about 3 μg / mm ² of the surface of the expandable portion 11 . The desired rate of release of the active ingredient from the coating 12 may be provided by a single type of micro-reservoirs or alternatively a mixture of micro-reservoirs of different sizes or with release properties that provide a desired release profile to the vessel wall.

In some embodiments, the Corning 12 further comprises PEG-lipids for hemocompatiblity. In some embodiments the coating 12 disclosed herein is configured to be delivered to the luminal surface or luminal wall of a blood vessel and left to release the drug there during vascular therapy, thus requiring hemocompatibility of the coating 12. In order to prevent dissolution of the coating 12 into the bloodstream prior to treatment of the vessel, it is desirable to prevent the initiation of adhesion of fibrin and platelets to the coating surface exposed to blood after initiation and delivery of significant clotting. Addition of PEG-lipids to a composition of cholesterol and phospholipids or fatty acids can be used to provide increased hemocompatibility of the regimen. The polymer surface grafted with PEG shows improved blood contact properties mainly by lowering the interfacial free energy and by steric hindrance of the PEG chain hydrated on the surface. Without wishing to be bound by any particular theory of operation, small amounts of PEG-lipid complexes added to the composition may migrate to the blood interface surface after delivery, particularly for PEG-lipids of relatively small molecular weight. The PEG chain can thus lower the interfacial free energy at the blood interfacing surface. Since the coating material at the blood or fluid interface is a small fraction of the total coating, a relatively small amount of PEG-lipid is required.

In some embodiments, the PEG-lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1, 2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy (polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanol Amine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 ( DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG-lipid is about 1% to about 30% by weight of the hydrophobic matrix 14 comprising the cholesterol, fatty acid or a combination of phospholipid and PEG-lipid. In other embodiments, the PEG-lipid is from about 2% to about 25%, from about 3% to about 20%, or from about 5% to about 10% by weight of the hydrophobic matrix 14. In some embodiments, the PEG-lipid content is about 12% or less.

In some embodiments, the coating 12 further comprises one or more additives. In some embodiments, the one or more additives are independently selected from a penetration enhancer and a stabilizer. For example, the Corning 12 may further include additives to promote performance, such as penetration enhancers. The penetration enhancer can help the diffusion of the active ingredient into the blood vessel wall, and can maximize the tissue delivery of the active ingredient. Suitable penetration enhancers may include surfactants, cationic excipients and cationic lipids. In some embodiments, the additive may be added to the hydrophobic matrix, micro-reservoirs, or both. In some embodiments, a stabilizer may be added to protect the drug during disinfection of the balloon catheter system and subsequent storage prior to use. Stabilizers may include antioxidants and free radical scavengers. Examples of stabilizers include gallic acid, propylgallate, tocopherols and tocotrienols (vitamin E), butylatedhydroxytoluene, butylatedhydroxyanisole , ascorbic acid, thioglycolic acid, ascorbyl palmitate, and EDTA.

In some embodiments, the coating 12 further comprises a third active ingredient, wherein the third active ingredient is external to or in a hydrophobic matrix 14 of the micro-reservoirs. The third active ingredient may be the same as or different from the first or second active ingredient in the plurality of micro-reservoirs. However, since the active ingredient(s) are mainly contained in micro-reservoirs and do not come into direct contact with the hydrophobic matrix 14, there is no need to solubilize or emulsify the active ingredient in the hydrophobic matrix 14 itself. Since the active ingredient(s) are predominantly contained in micro-reservoirs and do not come in direct contact with the hydrophobic matrix 14, in some embodiments, the hydrophobic matrix 14 itself contains an amphoteric component or an active ingredient affinity component. no need to do The hydrophobic matrix 14 can thus be optimized to have appropriate properties for resistance to blood or body fluid wash-off and adsorption to lumen surfaces or lumen walls for coating 12 delivery.

catheter

do. With reference to 2, also disclosed herein is a catheter 10 comprising an expandable portion 11 on an elongated body, the coating 12 described above of the expandable portion 11, and a release layer between the expandable portion 11 and the coating 12. In some embodiments, the release layer 15 is configured to release the coating 12 from the expandable portion 11 . An emissive layer 15 that does not mix with the coating 12 is preferred to maintain distinct layers. In some embodiments, a PEG complex lipid is used as the release layer 15 because the degree of hydrophilicity and compatibility with the active ingredient coating 12 can be adjusted by the choice of the lipid and PEG chain length. In some embodiments, the release layer 15 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350) or 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550). In some embodiments, the emissive layer 15 is from about 0.1 μg/mm ² to about 5 μg/mm ² , from about 0.25 μg/mm ² to about 3 μg/mm ² , or from about 0.5 μg/mm ² to about 2 μg It has a surface concentration of /mm ² .

do. 3 , in some embodiments, the catheter 10 further comprises a protective layer 16 over the coating 12 as a top coat. In some embodiments, the protective layer 16 includes a hydrophilic polymer, a carbohydrate, or an amphoteric polymer. In some embodiments, the protective layer 16 is a glycosaminoglycan or crystallized sugar. Examples of glycosaminoglycans include dextran sulfate, chondroitin sulfate, heparan sulfate, and hyaluronic acid. Examples of crystallized sugars include mannitol, sorbitol, erythritol, and xylitol. The crystalline nature of these sugars provides a hard surface that protects the underlying micro-reservoirs. The thickness of the protective layer 16 may be adjusted to wash away the protective layer 16 during the transition time required for the catheter 10 to advance to the target location. In some embodiments, the protective layer 16 is about 0.1 μg/mm ² to about 5 μg/mm ² , about 0.2 μg/mm ² to about 4 μg/mm ² , or about 0.3 μg/mm ² to about 3 μg It has a surface concentration of /mm ² .

The expandable portion 11 of the catheter 10 may be a balloon, which serves as a substrate for the coating 12 . In some embodiments, the balloon may be a low pressure design using an elastic material such as polyisoprene, polystyrene copolymers, polysiloxane, or polyurethane. In some embodiments, the balloon may also be a high pressure design using high tensile polymers such as polyvinylchloride, polyethylene, polyethylene terephthalate, or nylon. . In some embodiments, the expandable portion 11 may be made of nylon 12. The coating 12 is sufficiently adherent to the expandable portion 11, but readily transfers to the tissue of the vascular lumen on contact. In addition, nylon 12 has sufficient strength to allow the balloon to further act as a post-dilatation balloon (if necessary) in subsequent procedures after delivery of the coating 12.

In some embodiments, the expandable portion 11 under the coating 12 may be used to inflate the target vessel. In some embodiments the vessel may be pre-dilated with another balloon catheter 10 prior to treatment with the coated balloon of the present embodiments.

prescription for coating

A formulation for coating for the expandable portion 11 of the catheter 10 is also disclosed herein. The formulation includes a solid portion and a fluid. The solid portion comprises a plurality of micro-reservoirs and at least one hydrophobic compound. The fluid acts to disperse or solubilize the at least one hydrophobic compound. In some embodiments, the fluid is capable of dispersing some hydrophobic compounds and solubilizing other hydrophobic compounds. The micro-reservoirs are dispersed and suspended in the resulting fluid mixture to form a formulation for the coating. The fluid mixture may be formulated to form a homogeneous mixture of the hydrophobic compounds that do not separate during drying to give a uniform, conformal coating of the hydrophobic matrix 14 . The coating formulation is characterized by the mass of the solid fraction, which refers to all non-volatile components of the coating formulation except for the fluid which is subsequently evaporated during drying of the coating.

The micro-reservoirs contain active ingredients and polymers. Said active ingredient may be referred to as the first active ingredient or the third active ingredient described herein. The polymer may be a biodegradable or bioerodible polymer described herein or a second biodegradable or bioerodible polymer. In some embodiments, the active ingredient is mixed with or dispersed in the biodegradable or bioerodible polymer described herein. In some embodiments, the prescription may include one or more types of micro-reservoirs. For example, the plurality of micro-reservoirs may contain a primary active ingredient and a biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs may further comprise a second active ingredient. In some embodiments, the plurality of micro-reservoirs may also include a second biodegradable or bioerodible polymer.

The micro-reservoirs can be prepared by any means known for particle production including spray drying, coacervation, micromolding, and milling. All such processes begin by dissolving the active ingredient and polymer together in a suitable solvent such as acetonitrile or dichloromethane, and then removing the solvent in a controlled manner to form uniform particles. The particles may be further shaped by mechanical means. Processes that produce particles having a size distribution with a coefficient of variation of 10% or less are particularly useful for providing a more consistent rate of active ingredient release. Methods for making microspheres of uniform size include forming an emulsion of the microsphere material and substrate with through-holes of controlled size, as described in US 7,972,543 and US 8,100,348. It is described as extruding the emulsion through Alternatively, microspheres can be prepared by spray-drying the polymer, as described in US 6,560,897 and US 20080206349.

The fluid of the coating formulation may include water, an organic solvent, perfluorocarbon fluids, or a mixture of such fluids. In some embodiments, the fluid is selected from the group consisting of pentane, hexane, heptane, heptane and fluorocarbon mixtures, alcohol and fluorocarbon mixtures, and alcohol and water mixtures. Fluids that readily solubilize the active ingredient or polymer in the micro-reservoirs are undesirable as they can extract the active ingredient from the micro-reservoirs. Such undesirable fluids include acetic acid, acetonitrile, acetone, ethyl formate, cyclohexanone, DMSO, and chloroform. Optionally, the fluid/fluid blend may be selected to saturate the desired level of extracted active ingredient. Additional active ingredients identical to those present in the micro-reservoirs can be added to the fluid prior to presaturating the solution, thus reducing extraction from the micro-reservoirs during processing of the coating. .

In some embodiments, the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, and surfactants, and derivatives thereof. In some embodiments, the at least one hydrophobic compound comprises cholesterol and a fatty acid described herein. In other embodiments, the at least one hydrophobic compound comprises cholesterol and a phospholipid as described herein. In some embodiments, the formulation may also include the PEG-lipids described herein. In some embodiments, the formulation may further include additives such as penetration enhancers and stabilizers.

In some embodiments, the solid portion further comprises a third active ingredient external to the plurality of micro-reservoirs. In other words, the coating formulation may lead to a hydrophobic matrix 14 further comprising a third active ingredient. The active ingredient outside the micro-reservoirs may be the same or different from the active ingredient(s) in the micro-reservoirs. In some embodiments, the solid portion may further comprise a PEG-lipid. In some embodiments, the solid portion may further include the additives described herein.

In some embodiments, the concentration of the solid portion in the coating formulation is from about 1% to about 90% by weight. In some embodiments, the solids content of the coating formulation has a concentration of from about 2% to about 80% by weight, from about 3% to about 70% by weight, or from about 4% to about 60% by weight. In some embodiments for spray coating, the solid portion of the coating formulation has a concentration of about 2% to about 7% by weight. The solid portion of the formulation for coating comprises from about 10% to about 75%, from about 20% to about 65%, or from about 30% to about 55% by weight of the plurality of micro-reservoirs.

The coating composition may be prepared by forming a mixture of at least two hydrophobic compounds described herein and a plurality of micro-reservoirs. The plurality of micro-reservoirs contain a first active ingredient and a biodegradable or bioerodible polymer. wherein the at least two hydrophobic compounds comprise cholesterol and phospholipids or cholesterol and fatty acids, wherein the at least two hydrophobic compounds are present in an amount and proportion sufficient to deliver the coating from the expandable portion of the catheter to a luminal wall, such as a vessel wall. do. In some embodiments, the mixtures further comprise a PEG-lipid as described above.

how to coat

A method of coating the expandable portion 11 of the catheter 10 is also disclosed herein. The steps include disposing the formulation described herein on the surface of the inflated expandable portion 11 of the catheter 10, evaporating the fluid components of the coating formulation, and collapsing the expandable portion 11 includes steps. Placing the prescription on the surface of the inflated expandable portion 11 includes placing the prescription on the surface of the inflated expandable portion 11 . In some embodiments, the formulation is applied onto or on the inflated expandable portion 11 by spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing. It may be located over the portion 11 .

The coating formulation is prepared by mixing the coating ingredients in a fluid disclosed herein. In some embodiments, the micro-reservoirs are dispersed into the fluid formulation. Once thoroughly mixed, the coating formulation can be applied to the surface of the inflated inflatable portion 11 , such as a balloon, and allowed to dry to form the coating 12 . Application of the coating formulation may be repeated as needed to deposit the required amount of coating 12, typically in the range of about 5 mg to about 9 mg of coating 12 per mm ² of the balloon surface. have. The coating 12 is dried and the balloon is deflated and folded for introduction into the circulation. In some embodiments, the release layer has already been placed on the surface of the inflated expandable portion 11 and the coating formulation can be applied to the existing release layer and dried to form the coating 12 . However, the release layer is between the expanded expandable portion 11 and the coating 12 .

In some embodiments, the method may further comprise placing a release layer on the surface of the inflated expandable portion 11 . However, the coating formulation is located on the release layer, while the release layer is located on the surface of the inflated expandable portion 11 . The emissive layer is described above.

How to treat or prevent a condition

Also disclosed herein are methods of treating or preventing a condition at the treatment site. The method includes advancing a catheter 10 comprising an expandable portion 11 to the treatment site, inflating the expandable portion 11 to allow for contact between the coating and tissue at the treatment site, retracting the expandable portion 11 , and removing the catheter 10 . The expandable portion 11 is coated with the coating described herein. In some embodiments, the contact between the tissue and the coating results in delivery of the treatment site expandable portion 11 and at least a portion of the coating on the expandable portion 11 to the coating for a time of about 30 to about 120 seconds.

A catheter 10 having an expandable portion 11, such as a coated balloon catheter, is used herein to describe the concept of delivering an active ingredient or combination of active ingredients into a blood vessel. The coated balloon catheter is inflatable when folded to provide a small cross-sectional profile and to facilitate insertion of the catheter 10 through the skin, for example by the well known Seldinger technique. It is introduced into the blood vessel with part 11. After the expandable portion 11 of the catheter 10 is advanced to the diseased area of the vessel for treatment, the balloon is inflated and the coating is in firm contact with the vessel lumen. The coating has affinity for the luminal tissue surface and results in adsorption of a layer of the coating onto the vascular lumen. The expandable portion 11 may be inflated or expanded for a period of 30 seconds up to 2 minutes to facilitate adsorption and provide initial penetration of the active ingredient into the vessel wall. The expandable portion 11 can be repeatedly contracted and expanded as required with a period of time and treatment to manage vascular occlusion or tissue ischemia. The coating is delivered adhesively into the lumen of the vessel upon abundant inflation and firm contact of the balloon surface with the vessel lumen surface. Adsorption of the coating to the vascular surface transports the micro-reservoirs and delivers them to the vascular surface.

In some embodiments, the condition is selected from the group consisting of atherosclerosis, stenosis or reduced lumen diameter in a diseased vessel, restenosis, and in-stent restenosis. In some embodiments, the additional release layer described herein is positioned between the intumescent portion 11 and the coating.

While the present disclosure is directed to the treatment of restenosis associated with balloon inflation of blood vessels, the present invention relates to a variety of other luminal and respiratory tracts, gastrointestinal tracts, urinary tracts, reproductive organs and the body's hollow structures such as the lymphatic system. can be used to convey The coated device may be an inflatable balloon or other inflatable device. Alternatively, the device carrying the coating of the present invention may be a non-expandable device of an inflatable device used for treatment of a living body or any other type of expandable device.

Examples

Example 1

A drug comprising micro-reservoirs (microspheres) prepared by coacervation of a polylactic-co-glycolic acid copolymer containing sirolimus (rapamycin) was obtained.

Microsphere sample 1: 50% DL-lactide / 50% glycolide copolymer, average diameter 3.1 μm, SD 0.44 μm, 39 wt% rapamycin

Microsphere sample 2: 75% DL-lactide / 25% glycolide copolymer, mean diameter 3.2 μm, SD 0.76 μm, 40 wt% rapamycin

Microsphere sample 3: 50% DL-lactide / 50% glycolide copolymer, mean diameter 2.7 μm, SD 0.8 μm, 45 wt% rapamycin

Microsphere specimen 4: 75% DL-lactide / 25% glycolide copolymer, mean diameter 3.3 μm, SD 1.2 μm, 46 wt% rapamycin

Microsphere sample 5: 75% DL-lactide / 25% glycolide copolymer, mean diameter 4.1 μm, SD 0.61 μm, 25 wt% rapamycin

Microsphere sample 6: 75% DL-lactide / 25% glycolide copolymer, mean diameter 3.78 μm, SD 0.44 μm, 28.8 wt% rapamycin

Microsphere sample 7: 75% DL-lactide / 25% glycolide copolymer, mean diameter 3.8 μm, SD 0.34 μm, 27.7 wt% rapamycin

Microsphere sample 8: 75% DL-lactide / 25% glycolide copolymer, mean diameter 3.79 μm, SD 0.39 μm, 29.4 wt% rapamycin

The drug content of these micro-reservoirs was confirmed by HPLC quantitation. Typically, micro-reservoirs (1-5 mg) were weighed and dissolved in 1 ml acetonitrile, gently agitated at room temperature for several hours or at 37°C for 1 hour, and 50-fold with acetonitrile. to 200-fold. Absorbance was observed at 278 nm and the content was determined from a linear calibration curve.

Example 2: physiological under the conditions from micro-reservoirs sustained drug release

The micro-reservoirs from Example 1 were tested for sustained release of the drug. Micro-reservoir specimens of 2 to 5 mg were placed in 1.6 ml Eppendorf tubes with 1.2 ml of phosphate buffered saline (PBS) to mimic the physiological environment. After an initial wash to remove any drug not contained in the micro-reservoirs, the tubes were incubated at 37°C with gentle mixing at 250 rpm. The PBS was sampled at timed intervals, and the released drug was quantified by reverse-phase HPLC using a C18 column.

Micro-reservoirs were analyzed for drug elution for 5 hours. The resulting drug release was consistent with the Korsmeyer-Peppas kinetic equation for drug release from a polymer with dispersed drug. The results of the Korsmeyer-Peppas model are shown in Table 1.

Table 1. Korsmeyer-Peppas Modeling of 5-Hour Drug Release

Q=a*x^b microsphere 1 microsphere 2 microsphere 3 microsphere 4 R (correlation coefficient) 0.9061 0.8778 0.8579 0.9016 Estimated SE 0.0026 0.0025 0.0021 0.0033 a 0.0450 0.0382 0.0305 0.0506 b 0.5241 0.5204 0.5167 0.4502

The short-time delivery results demonstrate that the Korsmeyer-Peppas drug release constant is universal for drugs dispersed in spherical polymer particles with the possibility of a small contribution due to polymer loss or degradation for microsphere specimens 1, 2, and 3.

Extended drug release study: Microspheres were analyzed for drug dissolution for 7 h using the methods described in the 5 h trial. The resulting drug release is shown in Table 2.

Table 2. 7-day drug release test

Cumulative drug release, % of total drug time [days] microsphere 1 microsphere 2 microsphere 3 microsphere 4 0 0.9% 1.5% 2.3% 2.2% One 1.8% 2.8% 3.3% 3.9% 2 2.3% 4.1% 4.0% 5.0% 3 4.2% 6.1% 4.6% 5.9% 4 5.7% 13.4% 5.2% 6.9% 5 7.5% 19.6% 5.8% 7.7% 6 10.0% 26.2% 6.4% 8.7% 7 11.9% 30.7% 7.0% 9.5%

The release rates from the 7-day transport results fit the Higuchi equation:

Q = A [D(2C - Cs)Cs t] ^1/2

Q = K _h (t) ^1/2

where Q is the amount of drug released at time t per unit area A, C is the initial concentration of the drug, Cs is the drug solubility in the polymer medium, and D is the dispersion coefficient of the drug in the microsphere polymer. In the generalized formula, K _h is the Higuchi constant including the above area, the coefficient of variance and the coefficient of drug concentration.

The Higuchi equation is used to determine the release half-life of the micro-reservoirs, and is also used to estimate the half-life as a function of the microsphere size. The resulting release half-lives are shown in Table 3.

Table 3. Drug release half-life by Higuchi modeling

microsphere diameter
[micron] t ^1/2 [number of days] microsphere 1 microsphere 2 microsphere 3 microsphere 4 0.5 0.14 0.02 0.42 0.11 One 2.29 0.34 6.65 1.70 1.5 11.58 1.71 33.66 8.61 2 36.60 5.42 106.38 27.22 3 185.29 27.43 538.53 137.81 4 585.62 86.71 1702.01 435.55 5 1429.74 211.69 4155.29 1063.36 6 2964.70 438.96 8616.42 2204.98 7 5492.48 813.22 15962.98 4084.99 8 9369.93 1387.32 27232.13 6968.81

The results indicate that the delivery half-life of a drug from micro-reservoirs can be adjusted by the prescription and size of the micro-reservoirs. It is estimated that for a transport half-life of at least 14 days, a microsphere size of 1.5 microns or greater will be required.

Proof of extended release: Microsphere sample 4 was analyzed for drug release for 8 weeks using previously described methods. Due to the relatively long time between sampling compared to previous release experiments, the micro-reservoirs may not have been released to sink at later time points, possibly slowing down the effective release rate. The resulting drug release is shown in Table 4.

Table 4. Extended drug release experiment over 56 days

time [days] Cumulative dissolution drug [%] 0 0 7 1.00 14 3.00 31 7.50 56 15.50

The results confirm sustained release of drug from the micro-reservoirs. Micro-reservoirs can be adjusted or selected with a half-life for providing drug through the healing time of the dilated blood vessels.

Example 3: Formula of micro-reservoirs in formulations for coating cholesterol and fatty acids with PEG-lipids

The coating formulation was made of DPPE-mPEG350 mixed with 107 mg of stearic acid, 105 mg of cholesterol, and 14 mL of heptane and heated to 60 °C to allow a clear solution to be prepared. The solution was then vortexed for 30 seconds and allowed to cool. Then, 200 mg of sirolimus containing the microspheres of sample #6 was added and the formulation was placed in an ultrasonic bath for 4 minutes to disperse and turbid the microspheres. [Prescription 1023E]

The coating formulation was prepared with 58 mg of erucic acid, 43 mg of DC-cholesterol, and 6.25 mg of DOPE-mPEG350 mixed with 7 mL of heptane and heated to 60 °C to make a clear solution. The solution was then vortexed for 30 seconds and allowed to cool. Then, 100 mg of sirolimus containing the microspheres of sample #8 was added and the formulation was placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0424A]

The coating formulation was prepared with 6.25 mg of DOPE-mPEG350 mixed with 25 mg of nervonic acid, 75 mg of DC-cholesterol, and 7 mL of heptane and heated to 60 °C to make a clear solution. The solution was then vortexed for 30 seconds and allowed to cool. Then, 97 mg of sirolimus containing the microspheres of sample #8 was added, and the formulation was placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0422E]

Example 4: Prescription of micro-reservoirs in formulations for coatings of cholesterol, fatty acids, PEG-lipids and sterilizing additives

The coating formulation was prepared with 77 mg of stearic acid, 40 mg cholesterol, 50 mg DPPE-mPEG350 and 58 mg of alpha-tocopherol mixed with 7 mL of heptane and heated to 60 °C to prepare a clear solution. The solution was then vortexed for 1 min and allowed to cool to room temperature. Then 100 mg of sirolimus containing the microspheres of sample #5 was added. The formulation was placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 1009A]

Example 5: Prescription of micro-reservoirs in formulations for coating of cholesterol and phospholipids

The coating formulation was prepared with 42 mg L-alpha-phosphatidylcholine mixed with 43 mg cholesterol and 7 mL of heptane and heated to 60 °C. The solution was then vortexed for 30 seconds and allowed to cool to room temperature. Then, 100 mg of sirolimus containing the microspheres of sample #5 was added to a vial and the vial was then placed in an ultrasonic water bath for 8 minutes to disperse and turbid the microspheres. [Prescription 0311A]

Example 6: Prescription of micro-reservoirs in formulations for coating of long acyl chain phospholipids with and without cholesterol and PEG-lipids

The coating formulation was prepared with 51 mg dierucoyl phosphatidylcholine (DEPC) mixed with 51 mg DC-cholesterol, 6.25 mg DOPE-mPEG350 and 7 mL heptane and heated to 60 °C. The solution was then vortexed for 30 seconds and allowed to cool to room temperature. Then, 100 mg of sirolimus containing the microspheres of sample #7 was added to the vial and then the vial was placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0410A]

The coating formulation was prepared with 75 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 20 mg DC-cholesterol, 26 mg cholesterol, 6.25 mg DOPE-mPEG350 and 7 mL heptane and heated to 60 °C. The formulation had a weight ratio of DNPC to DC-cholesterol of 1.6:1. The solution was allowed to cool to room temperature. Then, 97 mg of sirolimus containing the microspheres of sample #7 was added to the vial and then the vial was vortexed for 30 seconds and then an ultrasonic bath for 5 minutes for dispersion and turbidity of the microspheres. was placed on [Prescription 0421A]

The coating formulation was prepared with 50 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 28 mg DC-cholesterol, 26 mg cholesterol, 6.25 mg DOPE-mPEG350 and 7 mL heptane and heated to 60 °C. The solution was then vortexed for 30 seconds and allowed to cool to room temperature. Then, 97 mg of sirolimus containing the microspheres of sample #7 was added to the vial and then the vial was placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0421B]

The coating formulation was prepared with 50 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 50 mg DC-cholesterol and 7 mL of heptane and heated to 60 °C. The formulation had a weight ratio of DNPC to DC-cholesterol of 1:1. The solution was then vortexed for 30 seconds and allowed to cool to room temperature. Then, 100 mg of sirolimus containing the microspheres of sample #7 was added to the vial and then the vial was placed in an ultrasonic water bath for 4 minutes to disperse and turbid the microspheres. [Prescription 1205A]

The coating formulation was prepared with 50 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 49 mg DC-cholesterol, 6.25 mg DOPE-mPEG350 and 7 mL heptane and heated to 60 °C. The formulation had a weight ratio of DNPC to DC-cholesterol of 1:1. The solution was vortexed for 30 seconds and allowed to cool to room temperature. Then, 100 mg of sirolimus containing the microspheres of sample #7 was added to the vial and then the vial was placed in an ultrasonic water bath for 2 minutes to disperse and turbid the microspheres. [Prescription 1209A]

The coating formulation was prepared with 25 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 76 mg DC-cholesterol, 6.25 mg DOPE-mPEG350 and 7 mL heptane and heated to 60 °C. The formulation had a weight ratio of DNPC to DC-cholesterol of 1:3. The solution was allowed to cool to room temperature. Then, 100.7 mg of sirolimus containing the microspheres of sample #8 was added to the vial and then the vial was placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0513A]

Example 7: PEG -Prescription of micro-reservoirs in the formulation for coating DC-cholesterol with varying lipid content

The coating formulation was prepared with 44 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 12.5 mg DOPE-mPEG350, 44 mg DC-cholesterol and 7 mL heptane and heated to 60 °C. The clear solution was allowed to cool to room temperature, then 97 mg of silolimus containing microspheres from microsphere sample #8 was added. The formulation was then placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0422A]

The coating formulation was prepared with 37.5 mg dinerbornyl phosphatidylcholine (DNPC) mixed with 25 mg DOPE-mPEG350, 37.5 mg DC-cholesterol and 7 mL of heptane and heated to 60 °C. The clear solution was allowed to cool to room temperature, then 97 mg of silolimus containing microspheres from microsphere sample #8 was added. The formulation was then placed in an ultrasonic water bath for 5 minutes to disperse and turbid the microspheres. [Prescription 0422B]

Example 8: Coatings with additional drugs

The coating formulation was prepared with 72.9 mg DC-cholesterol in 7 mL of heptane and heated to 60°C until the DC-cholesterol was solubilized to prepare a clear solution. 15.5 mg of sirolimus was added to the solution and vortexed for 30 seconds. The solution was heated for 40 minutes, vortexed for 10 seconds every 10 minutes and sonicated for 5 minutes while cooling to room temperature. 50 mg of DNPC was added to the solution. At room temperature, the solution was filtered through a 0.2 micron PTFE filter to remove large drug particles. The solution was left overnight, with no particulates observed overnight. The solution was analyzed and the sirolimus content was 0.96/ml. To the solution was added 98 mg of sirolimus containing microspheres of microsphere sample #8, vortexed for 30 seconds and sonicated for 8 minutes to disperse and turbid the microspheres. The resulting coating formulation containing 0.71% by weight sirolimus of 19.1% of the drug is in the DC-cholesterol and DNPC hydrophobic mattress remaining in the microspheres. [Prescription 0512A]

The weight percent compositions of the coating formulations described in Examples 3, 4, 5, 6, 7 and 8 are shown in Table 5.

Table 5. Weight % compositions of formulations for coating

prescription for coating fatty acids or phospholipids cholesterol PEG-lipids microspheres Etc heptane sirolimus [%] [%] [%] [%] [%] [%] [%] 1023E stearic acid cholesterol DPPE-mPEG350 1.07% 1.05% 0.50% 2.01% 95.37% 0.58% 0424A erucic acid DC cholesterol DOPE-mPEG350 1.17% 0.87% 0.13% 2.01% 95.82% 0.59% 0422E nerbonic acid DC cholesterol DOPE-mPEG350 0.50% 1.51% 0.13% 1.96% 95.90% 0.57% 1009A stearic acid cholesterol DPPE-mPEG350 alpha tocopherol 1.52% 0.79% 0.98% 1.97% 1.14% 93.60% 0.45% 0311A L-alpha phosphatidyl-choline cholesterol 0.85% 0.87% 2.02% 96.26% 0.47% 0410A DEPC DC cholesterol DOPE-mPEG350 1.03% 1.03% 0.13% 2.01% 95.81% 0.56% 0421A DNPC Cholesterol/DC Cholesterol DOPE-mPEG350 1.51% 0.52%/0.40% 0.13% 1.95% 95.50% 0.54% 0421B DNPC Cholesterol/DC Cholesterol DOPE-mPEG350 1.01% 0.52%/0.56% 0.13% 1.95% 95.82% 0.54% 1205A DNPC DC cholesterol 1.01% 1.01% 2.02% 95.96% 0.56% 1209A DNPC DC cholesterol DOPE-mPEG350 1.01% 0.99% 0.13% 2.02% 95.86% 0.56% 0513A DNPC DC cholesterol DOPE-mPEG350 0.50% 1.53% 0.13% 2.03% 95.81% 0.60% 0422A DNPC DC cholesterol DOPE-mPEG350 0.89% 0.89% 0.25% 1.96% 96.01% 0.58% 0422B DNPC DC cholesterol DOPE-mPEG350 0.76% 0.76% 0.50% 1.96% 96.02% 0.58% 0512A DNPC DC cholesterol Sirolimus in a hydrophobic matrix 1.00% 1.46% 1.97% 0.13% 95.43% 0.71%

Example 9: Application of a coating formulation to a balloon catheter

The formulation for stearic acid coating of Example 3 (Formulation 1023E) was sprayed onto the balloon surface of 5.0 mm diameter X 20 mm length nylon dilatation balloons. 7 ml of the coating formulation was loaded into a 25 mL gas-tight syringe with an integrated magnetic stir bar system. The formulation was continuously agitated while spraying to maintain well-suspended drug micro-reservoirs. A syringe pump delivered the coating formulation at a rate of 0.11 mL/min through a 120 kHz ultrasonic nozzle activated with an output of 55 watts [Sonotek DES1000]. To verify the process parameters, a 5.0 mm diameter x 20 mm long cylinder of balloon material was cut, weighed and placed in a balloon of the same size. This sleeve of balloon material was then coated and weighed to ensure that about 2.2 mg of total coating was applied, which corresponds to a coating density of 7 μg/mm ² . 7 μg/mm ² of this formulation of Example 3 Among them, stearic acid contained about 1.6 μg/mm ² , cholesterol contained 1.6 μg/mm ² , and sirolimus containing microspheres of DPPE-mPEG350 0.8 μg/mm ² and microsphere sample #5 was 3 μg/mm was ² , This results in a drug density of 0.87 μg/mm ² . Once the sleeve weight identified for the target weight was achieved, the entire balloons were coated. A 5.0 mm diameter x 20 mm long balloon was inflated, placed under the spray and then rotated continuously for 5 back and forth movements. The balloon was then removed and dried. The process was repeated until 6 balloons were coated. This same procedure was repeated to spray the coating formulation of Example 6 (Formulation 0513A) on 3.0 mm diameter x 20 mm long balloons. The sleeve coating target weight was 1.4 mg to achieve a coating density of 7.6 μg/mm ² for a 3.0 mm diameter x 20 mm length balloon with the formulation of Example 6 (prescription 0513A). Of this 7.6 μg/mm ² , dinerbornyl phosphatidylcholine contained 0.9 μg/mm ² , DC-cholesterol 2.7 μg/mm ² , DOPE-mPEG350 0.23 μg/mm ² , and microspheres of sample #5. The sirolimus contained 3.7 μg/mm ² , resulting in a drug density of 1.08 μg/mm ² .

The coating formulations of Examples 4, 5, 6, 7 and 8 were sprayed onto the surface of 20 mm long balloons in the manner of spraying the formulation of Example 3 described above. The resulting coating weights and coating densities are shown in Table 6.

Table 6. Coating of balloon catheters

Example Prescription balloon diameter Prescription for Coatings % Solids (w/w) coating weight coating density cholesterol density Fatty acid or phospholipid density PEG-lipid density microsphere density drug density [mm] [%] [mg] [ug/mm ² ] [ug/mm ² ] [ug/mm ² ] [ug/mm ² ] [ug/mm ² ] [ug/mm ² ] 3 1023E 5 4.86% 2.19 6.97 1.58 1.61 0.75 3.02 0.87 3 424A 5 4.36% 2.05 6.53 1.35 1.83 0.20 3.15 0.93 3 0422E 5 4.27% 1.82 5.79 2.14 0.71 0.18 2.76 0.81 4 109A/
1010D 5 6.83% 2.54 8.09 1.00 1.92 1.24 2.49 0.57 5 0311A 5 3.89% 1.7 5.41 1.26 1.23 0.00 2.93 0.67 6 410A 5 4.38% 2.31 7.35 1.80 1.80 0.22 3.53 0.98 6 0421A 5 4.71% 1.88 5.98 1.23 2.00 0.17 2.59 0.72 6 0421B 5 4.36% 1.83 5.83 1.52 1.41 0.18 2.73 0.76 6 1205A 5 4.20% 1.78 5.67 1.42 1.42 0.00 2.83 0.78 6 1209A 5 4.32% 2.24 7.13 1.70 1.74 0.22 3.47 0.96 6 513A 3 4.37% 1.43 7.59 2.77 0.91 0.23 3.67 1.08 7 0422A 5 4.15% 1.8 5.73 1.28 1.28 0.36 2.81 0.83 7 0422B 5 4.14% 1.83 5.83 1.11 1.11 0.74 2.87 0.84 8 512A 3 4.79% 1.51 8.01 2.57 1.76 0.00 3.45 1.25

For the balloons coated with the formulation of Example 4, each balloon was sprayed with an additional top coat formulation (1010D) consisting of 1 mg of cholesterol and cholesterol-PEG6000 to cover the micro-reservoir layer. To make this top coating, 23 mg of cholesterol-PEG600 and 224 mg of cholesterol were dissolved in 7 mL of isopropanol. A target coating weight of 1 mg on the 5.0 mm diameter x 20 mm long balloon corresponds to 3.2 μg/mm ² of the total top coating consisting of 0.3 μg/mm ² cholesterol-PEG600 and 2.9 μg/mm ² cholesterol.

Example 10: Adsorption of coatings to vascular lumen surfaces

Ex-vivo porcine arteries were flushed with Lactated Ringer's solution at 37 °C in a pulsating blood flow of 50 mL/min (approximately 72 BPM) for 5 min. The balloons coated with the formulation of Example 3 were inflated to overstretch approximately 1:1.2 in the lumen of the porcine artery ex vivo to deliver the drug coating into the vascular lumen. Before and after inflation (before and after submersion), the solution passed through the artery, the balloon used for the artery, and the portion of the artery in contact with the inflated balloon were then dosed with drug 5 minutes after dilation submersion. analyzed. The vessels treated with formulations 1205A and 1209A were immersed for a total of 60 minutes to evaluate the expansion stability of the delivered coating. The drug content measured from all sources in the analysis was summed and compared to the estimated drug content of the balloon based on coating weight. The proportion of drug delivered to the artery based on the estimated drug content of the balloon by the coating weight was used as a measure of delivery efficiency.

Table 7. Stearic Acid-Cholesterol Prescription [Prescription 1023E]

balloon specimen Recovered sirolimus [ug] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 53 12 110 10 9 66 207 16 54 27 120 10 19 90 266 22 55 30 87 7 26 136 286 33 56 23 177 10 6 53 269 13 57 37 186 9 6 99 337 24 58 16 148 10 0 38 212 9 Average 24.2 138.0 9.3 11.0 80.3 262.8 19.5 SD 9.2 39.17 1.2 9.6 35.5 48.6 9

Table 8. Erusic Acid - DC-Cholesterol Prescription [Prescription 0424A]

balloon specimen recovered sirolimus [ug] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0424A-1 One 4 One 160 8 185 3 0424A-2 2 5 2 214 12 247 5 0424A-3 2 9 One 253 7 290 3 Average 1.8 5.9 1.5 209.2 8.8 240.8 3.9 SD 0.4 2.7 0.8 46.7 2.9 53.0 1.3

Table 9. Nervonic Acid - DC-Cholesterol Prescription [Prescription 0422E]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0422E-1 5 28 6 128 62 229 22 0422E-2 3 39 4 90 35 171 12 0422E-3 16 8 4 76 84 187 29 Average 8 25 4 98 61 196 21.2 SD 7 16 One 27 25 30 8.6

Balloons coated with the formulation of Example 4 were also tested in ex vivo porcine arteries.

Table 10. Stearic Acid-Cholesterol-Alpha Tocopherol Prescription [Prescription 1009A/1010D]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 40 N/A 78 3 354 28 463 6 41 12 120 4 301 31 468 6

Balloons coated with the formulation of Example 5 were also tested in ex vivo porcine arteries.

Table 11. L-alpha-phosphatidylcholine - cholesterol prescription [prescription 0311A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0311A-1 51 60 4 12 26 153 9 0311A-2 100 74 4 25 7 210 2 0311A-3 44 92 5 26 45 212 15 Average 65.0 75.3 4.3 21.0 26.0 191.7 8.7 SD 30.5 16.0 0.6 7.8 19.0 33.5 6.5

Balloons coated with the formulation of Example 6 were also tested in ex vivo porcine arteries.

Table 12. DEPC - DC-Cholesterol [Prescription 0410A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0410A-1 17 21 3 12 196 249 52 0410A-2 34 12 2 15 228 290 60 0410A-3 17 30 One 14 137 199 53 Average 65 75 4 21 26 192 55 SD 31 16 One 8 19 34 6.3

Table 13. DNPC - DC-Cholesterol Prescription [Prescription 0421A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0421A-1 16 6 One 32 127 259 40% 0421A-2 18 13 3 29 114 240 35% 0421A-3 21 9 7 24 138 264 43% Average 18.4 9.4 3.6 28.4 126.4 254.4 39.4% SD 2.7 3.6 2.7 4.2 12.2 12.5 3.8%

Table 14. DNPC-DC-Cholesterol-Cholesterol Prescription [Prescription 0421B]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0421B-1 8 16 One 120 131 276 45 0421B-2 5 21 2 196 108 331 37 0421B-3 4 22 5 137 83 250 28 Average 5.3 19.7 2.7 151.2 107.1 286.0 36.7 SD 2.1 2.9 2.0 39.9 23.9 41.3 8.2

Table 15. DNPC-DC-Cholesterol (no PEG-Lipid) Prescription [Prescription 1205A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 106 14 47 3 94 168 326 47 105 10 84 5 142 165 406 46 107 8 68 4 100 147 327 41 108 9 43 4 121 144 321 41 109 4 66 9 62 158 299 45 110 3 52 One 128 126 310 35 Average 8.0 60.0 4.3 107.8 151.3 331.5 42.5 SD 4.0 15.5 2.7 28.6 15.6 38.0 4.5

Table 16. [DNPC-DC-Cholesterol (PEG-Lipid) Prescription [Prescription 1209A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 124 5 64 One 30 148 248 38 125 5 79 4 88 158 334 41 126 4 45 9 144 152 354 39 127 8 73 5 135 124 345 32 128 2 49 5 98 190 344 49 129 4 89 5 90 149 337 38 Average 4.7 66.5 4.8 97.5 153.5 327.0 39.5 SD 2.0 17.2 2.6 40.7 21.3 39.3 5.5

Table 17. DNPC-DC-Cholesterol (PEG-Lipid) Prescription [Prescription 0513A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0513A-1 6 4 One 134 67 212 30% 0513A-2 5 12 2 150 85 254 38% 0513A-3 5 2 One 152 88 248 39% Average 5.3 6.0 1.3 145.3 80.0 238.0 35.4% SD 0.6 5.3 0.6 9.9 11.4 22.7 5.0%

The luminal surface of the artery was observed under darkfield microscopy after inflation of the balloon coated with formulation 1209A and 1 hour after immersion in inflation fluid. 4 is a micrograph of the lumen surface at 200X magnification showing the adsorbed material. do. 5 is a photomicrograph of the surface at 1000X magnification showing the adsorbed material being a layer of spherical micro-reservoirs surrounded by a coating material.

Example 11: Vascular lumen of formulations with varying PEG-lipid content Adsorption of the coating to the surface

Samples from Example 7 were tested for coating delivery and resistance to wash-off using the methods of Example 10. The results have been tabulated to compare the coatings with equal weight ratios of DNPC and DC-cholesterol with varying amounts of DOPE-mPEG350. [Prescriptions 1205A, 1209A, 0422A, 0422B]

Table 18. Resistance to coating transfer and wash-off for various coating regimens

Prescription Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery No PEG-lipids 8.0
± 4.0 60.0
± 15.5 4.3
± 2.7 107.8
± 28.6 151.3
± 15.6 331.5
± 38.0 42.5
± 4.5 5.9% mPEG 350 4.7
± 2.0 66.5
± 17.2 4.8
± 2.6 97.5
± 40.7 153.5
± 21.3 327.0
± 39.3 39.5
± 5.5 12.4% mPEG 350 6.5
± 3.2 38.9
± 21.0 4.5
± 0.6 107.4
± 35.5 90.4
± 29.2 247.6
± 55.1 30.0
± 9.7% 25% mPEG 350 25.0
± 26.1 68.3
± 36.7 6.2
± 3.2 17.9
± 12.0 106.7
± 19.8 224.1
± 27.8 36.0
± 6.7%

The results indicate significant delivery of the drug coating into the vascular lumen. Drug coating loss during pre-immersion was increased for formulations for coatings with 25% PEG-lipids.

Example 12: additional ramaphicin Vascular lumen of coating with adsorption to the surface

The formulation of Example 8 was tested for resistance to coating transfer and washing using the method of Example 10.

Table 19. DNPC-DC-Cholesterol Prescription with Additional Drugs [Prescription 0512A]

balloon specimen Recovered sirolimus [μg] Total sirolimus recovered [μg] % of total sirolimus on balloon delivered arterially 1 minute before immersion 1 minute after submersion 2 minutes after submersion balloon residue artery 0512A-1 3 43 2 155 76 279 29% 0512A-2 5 9 10 51 39 114 15% 0512A-3 6 8 2 135 47 198 18% Average 4.7 20.0 4.7 113.7 54.0 197.0 20.9% SD 1.5 19.9 4.6 55.2 19.5 82.5 7.5%

The results indicate a significant delivery of the drug from the coating to the lumen of blood vessels with the drug added to the phospholipid and cholesterol components of the coating formulation.

Example 13: Drug release into treated blood vessels in-vivo

To prepare balloon catheters coated with drug micro-reservoir containing prescription, 100 mg DNPC, 103 mg DC-cholesterol and 12.5 mg DOPE-mPEG350 were mixed in 14 mL of heptane. The mixture was heated to 60 °C and cooled to room temperature to dissolve the solid components. Then 195 mg of microsphere sample #6 was added and stirred to suspend the microspheres. Balloon catheters with 3.0 mm diameter x 20 mm long balloons were coated with the formulation using the methods described in Example 9. The coated balloon catheters were dried. An average of 1.28 mg ± 0.12 mg of dried coating was applied to the balloons, resulting in a coating density of 6.80 μg/mm ² , resulting in a drug density of 1.06 μg/mm ² . The balloon was deflated and folded into a pre-launched configuration with a smaller cross-sectional area and packaged with a sleeve to maintain the folded configuration. The balloon catheters were packed and disinfected by ionizing radiation in an amount of at least 25 kiloGray.

Rabbit iliac-femoral arteries were used to evaluate the in vivo metastasis of the drug coating to arterial vessels. The portion of the iliac-femoral artery for treatment was first stripped of the endothelium to create tissue damage before dilatation. An incision was made in the common carotid artery and a size 5F balloon wedge catheter was inserted into the artery and guided under fluoroscopic guidance to the treatment site of the iliac femoral artery. A contrast agent was inserted through the catheter and the vascular illumination of the iliac femoral artery was recorded. The balloon wedge catheter was replaced with a 3.0 mm diameter x 8 mm long standard dilatation balloon catheter under the guidance of a fluoroscope, inflated and withdrawn close to the degree of iliac bifurcation for dissection of the artery in an inflated state. The dilatation balloon catheter was replaced with a drug coated balloon catheter. The catheter was advanced into the ablated vessel portion and inflated for 120 seconds. The balloon was deflated and withdrawn. Both the left and right iliac arteries of each animal were tested.

A total of 11 animals were treated. One animal (2 iliac arteries treated) was euthanized 1 hour after treatment and vascular sections were restored for microscopic examination. Another animal (2 iliac arteries treated) was euthanized 24 hours after treatment and vascular sections were restored for microscopic examination. Three animals (6 iliac arteries) recovered at 1 hour, 7 days and 28 days, respectively. Blood samples were taken from these animals prior to surgery at 0.5, 1, and 4 hours before treatment and at the time of sacrifice. The vascular sections were recovered and analyzed for drug content by HPLC/MS quantitation.

Analysis of blood samples revealed a sharp decrease in drug in the circulating blood to 4.75 ng/ml at 30 min, 2.63 ng/ml at 1 h and 0.82 ng/ml at 4 h. The blood concentrations of drug collected for the Day 7 and Day 28 time points at the time of sacrifice were below the detection limit for the quantitation assay. The blood levels fit an exponential decay curve with a half-life of 0.77 hours, indicating rapid dilution and clearance of the drug from the bloodstream.

Electron microscopy and light microscopy of the tissue specimens collected 1 and 24 hours after treatment showed that a layer of material on the vascular lumen surface had spherical drug micro-reservoirs observed within the layer. Although uneven areas of fibrin were observed on the luminal surface, no large fibrin deposits related to the coating, indicative of blood incompatibility, were observed.

Analysis of the treated vascular sections was 261 μg/g ± 116.5 μg/g at 1 hour post treatment, 43.8 μg/g ± 34.2 μg/g at 7 days post treatment and 21.5 μg/g ± 17.3 μg at 28 days post treatment. tissue drug levels of /g. The results indicate that the drug containing the micro-reservoir coating has a sustained presence of the drug associated with the tissue of the treated blood vessel for 28 days, and adsorption to the luminal surface of the artery. The tissue associated with drug levels showed a rapid, initial decline, delayed between 7 and 28 days. Tissues related to drug levels from the 7th and 28th days were suitable for exponential decline, and showed a half-life of about 20.4 days.

additional embodiments

Although the present invention has been disclosed in terms of certain preferred embodiments and examples, those of ordinary skill in the art will recognize that the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the present invention and obvious ones. It will be understood to extend to variations and equivalents thereof. Additionally, aspects and forms of the invention described may be practiced separately, in combination, or substituted for one another, and that various combinations and subcombinations of the above aspects and aspects may be made and still present the present invention. It is contemplated that they are within the scope of the invention. Moreover, the above disclosure herein in connection with any particular form, aspect, method, attribute, feature, quality, quality, element, and practice may be used in all other embodiments set forth herein. Accordingly, the scope of the invention disclosed herein should not be limited by the specific disclosed embodiments described above, but should be determined only by a sound reading of the claims.

such as "could", "might", or "may", among other things, particularly otherwise understood in the context in which it was stated or used; Stateful language is typically intended to convey that certain embodiments include certain forms or elements, even if other embodiments do not. Accordingly, such stateful language is not intended to imply that typically forms or elements are in any manner required for one or more embodiments.

Summary of Examples

A coating for an expandable portion of a catheter comprising a dispersed phase and a hydrophobic matrix comprising a plurality of micro-reservoirs dispersed in a hydrophobic matrix, wherein the plurality of micro-reservoirs comprises a first active ingredient and a biodegradable or bioerodible polymer . The coating is configured to transfer into the lumen when the expandable portion is inflated.

In the embodiments of the coating described above, the first active ingredient is mixed with or dispersed in the biodegradable or bioerodible polymer.

In embodiments of the coating described above, the biodegradable or bioerodible polymer is polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosoaminoglycans, and combinations thereof.

In embodiments of the coating described above, the hydrophobic matrix comprises at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

In some embodiments of the coating described above, wherein the hydrophobic matrix comprises cholesterol and fatty acids. In some embodiments, the weight ratio of cholesterol to fatty acid ranges from about 1:2 to about 3:1.

In embodiments of the coating described above, the fatty acid is lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid (myristic acid), myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid , linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, Mead acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid , tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.

In other embodiments of the coating described above, it comprises the hydrophobic matrix cholesterol and phospholipids. In some embodiments, the weight ratio of cholesterol to phospholipid ranges from about 1:2 to about 3:1.

In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatiethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine.

In some embodiments, the phospholipid comprises an acyl chain of about 20 to about 34 carbons in length. In some embodiments, the phospholipid is dieicosenoyl phosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine) ), C20:1 PC), diarachidonoyl phosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine) ), C20:0 PC), dierucoyl phosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine (1,2-dierucoyl-sn-glycero-3- phosphocholine), C22:1 PC), didocosahexaenoyl phosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (1,2-didocosahexaenoyl-sn-glycero) -3-phosphocholine), C22:6 PC), heneicosenoyl phosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine (1,2-heneicosenoyl- sn-glycero-3-phosphocholine), C21:1 PC) and dinervonyl phosphatidylcholine (1,2-dinerobonoyl-sn-glycero-3-phosphocholine (1,2-dinervonoyl) -sn-glycero-3-phosphocholine), C24:1 PC).

In embodiments of the coating described above, the cholesterol is DC-cholesterol.

In embodiments of the coating described above, the plurality of micro-reservoirs is from about 10% to about 75% by weight of the coating.

In embodiments of the coating described above, the plurality of micro-reservoirs have an average diameter of about 1.5 microns to about 8 microns. In some embodiments, the plurality of micro-reservoirs have an average diameter of about 2 microns to about 6 microns. In some embodiments, the plurality of micro-reservoirs have an average diameter of about 3 microns to about 5 microns.

In embodiments of the coating described above, the plurality of micro-reservoirs have an active ingredient release rate with a half-life of at least 14 days.

In embodiments of the coating described above, the first biodegradable or bioerodible polymer is polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin , chitosan, glycosoaminoglycans, and combinations thereof.

In embodiments of the coating described above, the first active ingredient is paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogue, sirolimus analogue, inhibitory RNA, is selected from the group consisting of inhibitory DNA, steroids, and complement inhibitors.

In embodiments of the coating described above, the first active ingredient is from about 10% to about 50% by weight of the plurality of micro-reservoirs.

In embodiments of the coating described above, the coating further comprises a second active ingredient external to the plurality of micro-reservoirs. In some embodiments, the second active ingredient consists of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. selected from the group. In some embodiments, the second active ingredient is the same as the first active ingredient.

In embodiments of the coating described above, the hydrophobic matrix further comprises a PEG-lipid. In some embodiments, the PEG-lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1, 2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy (polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanol Amine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 ( DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG-lipid is from about 1% to about 30% by weight of the hydrophobic matrix. In some embodiments, the PEG-lipid is about 12% or less by weight of the hydrophobic matrix.

In embodiments of the coating described above, the coating further comprises one or more additives independently selected from penetration enhancers and stabilizers.

In embodiments of the coating described above, wherein the coating has a surface concentration of about 1 μg/mm ² to about 10 μg/mm ² .

A catheter comprising an expandable portion on an elongated body and any embodiment of the coating described above on the expandable portion. In some embodiments, the catheter further comprises a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion. In some embodiments, the emissive layer comprises DSPE-mPEG350 or DSPE-mPEG500. In some embodiments, the emissive layer has a surface concentration of about 0.1 μg/mm ² to about 5 μg/mm ² .

In embodiments of the catheter described above, the catheter further comprises a protective coating over the coating. In some embodiments, the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphoteric polymer. In some embodiments, the protective coating is a glycosaminoglycan or crystallized sugar. In some embodiments. The protective coating has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² .

A formulation for coatings for the intumescent portion of a catheter containing a solid portion and a fluid. The solid portion comprises a plurality of micro-reservoirs and at least one hydrophobic compound, wherein the plurality of micro-reservoirs comprises a first active ingredient and a biodegradable or bioerodible polymer. In some embodiments the first active ingredient is mixed with or dispersed in the biodegradable or bioerodible polymer.

In some embodiments, the first active ingredient is from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. is selected from In some embodiments, the biodegradable or bioerodible polymer is polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosoaminoglycan , and combinations thereof.

In some embodiments of the coating formulation described above, the fluid is selected from the group consisting of pentane, hexane, heptane, heptane and fluorocarbon mixtures, alcohol and fluorocarbon mixtures, and alcohol and water mixtures.

In some embodiments of the coating formulation described above, wherein the solid portion further comprises a second active ingredient external to the plurality of micro-reservoirs. In some embodiments, the second active ingredient is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors. is chosen

In some embodiments of the coating formulation described above, wherein the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

In some embodiments of the coating formulation described above, wherein the at least one hydrophobic compound comprises cholesterol and a fatty acid. In some embodiments, the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3:1. In some embodiments, the fatty acid is lauric acid, lauroleic acid, tetradedienoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecanoic acid, palmitoleic acid, palmitic acid , linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, aracadonic acid, mad acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosapentaenoic acid, tetra It is selected from the group consisting of chosanic acid, hexacocenic acid, pristanoic acid, phytanic acid, and nervonic acid.

In some embodiments of the coating formulation described above, wherein the at least one hydrophobic compound comprises cholesterol and phospholipids. In some embodiments, the weight ratio of cholesterol to phospholipid ranges from about 1:2 to about 3:1. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or amine derivatives of phosphatidylcholine.

In some embodiments, the phospholipid comprises an acyl chain of about 20 to 34 carbons in length. In some embodiments, the phospholipid is dieicosenoyl phosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine) ), C20:1 PC), diarachidonoyl phosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine) ), C20:0 PC), dierucoyl phosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine (1,2-dierucoyl-sn-glycero-3- phosphocholine), C22:1 PC), didocosahexaenoyl phosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (1,2-didocosahexaenoyl-sn-glycero) -3-phosphocholine), C22:6 PC), heneicosenoyl phosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine (1,2-heneicosenoyl- sn-glycero-3-phosphocholine), C21:1 PC) and dinervonyl phosphatidylcholine (1,2-dinerobonoyl-sn-glycero-3-phosphocholine (1,2-dinervonoyl) -sn-glycero-3-phosphocholine), C24:1 PC).

In some embodiments of the coating formulation described above, the cholesterol is DC-cholesterol.

In some embodiments of the coating formulation described above, the solid portion further comprises a PEG-lipid, and/or an additive. In some embodiments, the PEG-lipid is 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2- dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy (polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine- N-methoxy (polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-550 (DSPE- mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550).

In some embodiments of the coating formulation described above, the plurality of micro-reservoirs is from about 10% to about 75% by weight of the solid portion.

In some embodiments of the coating formulation described above, the solid portion is about 2 to about 7% by weight of the coating formulation.

Coating an expandable portion of a catheter comprising the steps of placing the coating formulation of any of the embodiments described above on the surface of the inflated expandable portion of the catheter, evaporating the fluid, and deflating the expandable portion. How to. In some embodiments, positioning the formulation for coating comprises spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.

In some embodiments of the method described above, the method further comprises positioning an emissive layer on the expandable portion. In some embodiments, the emissive layer comprises DSPE-mPEG350 or DSPE-mPEG500.

advancing a catheter comprising an expandable portion to the treatment site, wherein the expandable portion is coated with a coating of any of the embodiments described above, and wherein the expandable portion is in contact between the coating and tissue at the treatment site. A method for treating or preventing a condition at a treatment site comprising inflating, retracting said expandable portion, and removing said catheter.

In embodiments of the method described above, the contact between the tissue and the coating results in delivery of at least a portion of the coating on the expandable portion to the treatment site. In some embodiments, the method further comprises maintaining contact between the coating and the tissue for a time of between about 30 seconds and about 120 seconds.

In embodiments of any of the methods described above, the condition is atherosclerosis, stenosis or reduction in lumen diameter in a diseased vessel, restenosis, in-stent restenosis, and combinations thereof. selected from the group consisting of

In embodiments of any of the methods described above, wherein an additional emissive layer is positioned between the intumescent portion and the coating.

Claims (72)

an expandable portion over an elongated body; and
A catheter comprising a coating over the expandable portion, the catheter comprising:
The coating is
a hydrophobic matrix, wherein the hydrophobic matrix comprises cholesterol and fatty acids or cholesterol and phospholipids;
a dispersed phase comprising a plurality of micro-reservoirs dispersed in said hydrophobic matrix, said plurality of micro-reservoirs comprising a first active agent and a biodegradable or bioerodible polymer; ;
When the expandable portion is inflated into a treatment site, the coating migrates in an adsorbing manner into the lumen of a vessel, wherein adhesion of the coating to the vessel removes at least a portion of the plurality of micro-reservoirs. to move to the luminal surface,
catheter. The catheter of claim 1 , wherein the first active ingredient is mixed with or dispersed in a biodegradable or bioerodible polymer. 3. The biodegradable or bioerodible polymer according to claim 1 or 2, wherein the biodegradable or bioerodible polymer is polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone. (polycaprolactone), polyphosphazene (polyphosphazene), collagen, gelatin, chitosan, glycosoaminoglycans (glycosoaminoglycans), and a catheter selected from the group consisting of combinations thereof. The catheter of claim 1 , wherein said hydrophobic matrix comprises cholesterol and fatty acids. 5. The catheter of claim 4, wherein the weight ratio of cholesterol to fatty acid is in the range of 1:2 to 3:1. 5. The method of claim 4, wherein the fatty acid is lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid, Myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid ), linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, mead acid ), arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanic acid ( A catheter selected from the group consisting of tetracosanoic acid), hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid. The catheter of claim 1 , wherein said hydrophobic matrix comprises cholesterol and phospholipids. 8. The catheter of claim 7, wherein the weight ratio of cholesterol to phospholipid is in the range of 1:2 to 3:1. 8. The catheter of claim 7, wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. 8. The catheter of claim 7, wherein said phospholipid is a cationic phospholipid. 11. The catheter of claim 10, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine. 8. The catheter of claim 7, wherein said phospholipid comprises an acyl chain of 20 to 34 carbons in length. 13. The method of claim 12, wherein the phospholipid is 1,2-dieicosenyl-sn-glycero-3-phosphocholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine), 1,2-diaraki Doyl-sn-glycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine), 1,2-dierucoyl-sn-glycero-3-phosphocholine (1 ,2-dierucoyl-sn-glycero-3-phosphocholine), 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine), 1,2-heneicosenoyl-sn-glycero-3-phosphocholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine), and 1,2-dynerobonoyl-sn-glycero A catheter selected from the group consisting of -3-phosphocholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine). 5. The catheter of claim 4, wherein said cholesterol is DC cholesterol. The catheter of claim 1 , wherein the plurality of micro-reservoirs is from 10% to 75% by weight relative to the weight of the solid components forming the coating. The catheter of claim 1 , wherein said plurality of micro-reservoirs have an average diameter of between 1.5 microns and 8 microns. 17. The catheter of claim 16, wherein said plurality of micro-reservoirs have an average diameter of between 2 microns and 6 microns. 17. The catheter of claim 16, wherein said plurality of micro-reservoirs have an average diameter of between 3 microns and 5 microns. The catheter of claim 1 , wherein said plurality of micro-reservoirs have an active ingredient release kinetic with a half-life of at least 14 days. According to claim 1, wherein the first active ingredient is paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogue, sirolimus analogue, inhibitory RNA, inhibitory DNA, steroid , and a catheter selected from the group consisting of complement inhibitors. The catheter of claim 1 , wherein said first active ingredient is between 10% and 50% by weight relative to the weight of said plurality of micro-reservoirs. The catheter of claim 1 , wherein the coating further comprises a second active ingredient on the exterior of the plurality of micro-reservoirs. 23. The method of claim 22, wherein said second active ingredient is paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogue, sirolimus analogue, inhibitory RNA, inhibitory DNA, steroid , and a catheter selected from the group consisting of a complement inhibitor. 24. The catheter of claim 22 or 23, wherein said second active ingredient is the same as said first active ingredient. The catheter of claim 1 , wherein said hydrophobic matrix further comprises a PEG-lipid. 26. The method of claim 25, wherein the PEG-lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1 ,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy (polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phospho Ethanolamine-N-methoxy (polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-550 (DSPE-mPEG550), 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl -sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol) -500 (DOPE-mPEG500) catheter selected from the group consisting of. 26. The catheter of claim 25, wherein said PEG-lipid is 1% to 30% by weight relative to the weight of said hydrophobic matrix. 26. The catheter of claim 25, wherein said PEG-lipid is 12 wt% or less relative to the weight of said hydrophobic matrix. The catheter of claim 1 , wherein the coating further comprises in the coating one or more additives independently selected from penetrating enhancers and stabilizers. The catheter of claim 1 , wherein the coating has a surface concentration of 1 μg/mm ² to 10 μg/mm ² . delete The catheter of claim 1 , further comprising a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion. 33. The catheter of claim 32, wherein said release layer comprises DSPE-mPEG350 or DSPE-mPEG500. The catheter of claim 32 , wherein the release layer has a surface concentration of 0.1 μg/mm ² to 5 μg/mm ² . The catheter of claim 1 , further comprising a protective coating layer over the coating. 36. The catheter of claim 35, wherein the protective coating layer comprises a hydrophilic polymer, a carbohydrate, or an amphoteric polymer. 36. The catheter of claim 35, wherein said protective coating layer is glycosaminoglycan or crystallized sugar. 36. The catheter of claim 35, wherein the protective coating layer has a surface concentration of 0.1 μg/mm ² to 5 μg/mm ² . a plurality of micro-reservoirs containing the first active ingredient and a biodegradable or bioerodible polymer; and a solid portion comprising at least one hydrophobic compound, and
contains a fluid,
wherein the at least one hydrophobic compound comprises cholesterol and fatty acids or cholesterol and phospholipids,
A formulation for coating for the expandable portion of a catheter. 40. The formulation according to claim 39, wherein said first active ingredient is mixed with or dispersed in said biodegradable or bioerodible polymer. 41. The method of claim 39 or 40, wherein the biodegradable or bioerodible polymer is polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, A coating formulation selected from the group consisting of glycosoaminoglycans, and combinations thereof. 40. The formulation of claim 39, wherein said fluid is selected from the group consisting of pentane, hexane, heptane, heptane and fluorocarbon mixtures, alcohols and fluorocarbon mixtures, and alcohol and water mixtures. 40. The formulation of claim 39, wherein said solid portion further comprises a second active ingredient outside said plurality of micro-reservoirs. 44. The method of claim 43, wherein said second active ingredient is paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogue, sirolimus analogue, inhibitory RNA, inhibitory DNA, steroid , And a formulation for coating that is selected from the group consisting of complement inhibitors. 40. The method of claim 39, wherein said first active ingredient is paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogue, sirolimus analogue, inhibitory RNA, inhibitory DNA, steroid , And a formulation for coating that is selected from the group consisting of complement inhibitors. 40. The formulation of claim 39, wherein said at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof. 40. The formulation of claim 39, wherein said at least one hydrophobic compound comprises cholesterol and a fatty acid. 48. The formulation according to claim 47, wherein the weight ratio of cholesterol to fatty acid is in the range of 1:2 to 3:1. 48. The method of claim 47, wherein the fatty acid is lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid, Myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid ), linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, mead acid ), arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanic acid ( tetracosanoic acid), hexacosenoic acid, pristanoic acid, phytanic acid, and nervonic acid. A coating agent selected from the group consisting of. 40. The formulation of claim 39, wherein said at least one hydrophobic compound comprises cholesterol and phospholipids. 51. The formulation according to claim 50, wherein the weight ratio of cholesterol to phospholipid is in the range of 1:2 to 3:1. 51. The coating formulation of claim 50, wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. 51. The formulation of claim 50, wherein the phospholipid is a cationic phospholipid. The coating formulation of claim 53, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine. 51. The formulation of claim 50, wherein said phospholipid comprises an acyl chain of 20 to 34 carbons in length. 56. The method of claim 55, wherein the phospholipid is 1,2-dieicosenoyl-sn-glycero-3-phosphocholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine), 1,2-diaraki Doyl-sn-glycero-3-phosphocholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine), 1,2-dierucoyl-sn-glycero-3-phosphocholine (1 ,2-dierucoyl-sn-glycero-3-phosphocholine), 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine), 1,2-heneicosenoyl-sn-glycero-3-phosphocholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine), and 1,2-dynerobonoyl-sn-glycero A formulation for coating that is selected from the group consisting of -3-phosphocholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine). The formulation for coating according to claim 47, wherein the cholesterol is DC cholesterol. 40. The formulation of claim 39, wherein the solid portion further comprises a PEG-lipid, and/or an additive. 59. The method of claim 58, wherein said PEG-lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1 ,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy (polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phospho Ethanolamine-N-methoxy (polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-550 (DSPE-mPEG550), 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl -sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-500 (DOPE-mPEG500) is selected from the group consisting of a coating formulation. 40. The formulation of claim 39, wherein said plurality of micro-reservoirs is from 10% to 75% by weight relative to the weight of said solid portion. The formulation for coating according to claim 39, wherein the solid portion is 2 to 7% by weight based on the weight of the formulation for coating. 41. A method comprising: placing the coating formulation of claim 39 on the surface of an expanded expandable portion of the catheter;
evaporating the fluid; and
collapsing the expandable portion;
A method of coating the expandable portion of a catheter. 63. The method of claim 62, wherein positioning the coating formulation comprises spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing. 63. The method of claim 62, wherein the release layer is disposed on the surface of the intumescent portion. 65. The method of claim 64, wherein said coating agent is positioned over said release layer. 65. The method of claim 64, wherein said emissive layer comprises DSPE-mPEG350 or DSPE-mPEG500. delete delete delete delete delete delete

Images